Cleft lip and palate is a common human developmental malformation that may require significant medical and surgical intervention. It is etiologically heterogeneous, being found as a component in over 100 individually rare syndromes and more commonly as isolated, non-syndromic cleft lip and palate (CL/P). Among the syndromic causes is Van der Woude Syndrome (VDWS) - a single gene autosomal dominant disorder that also includes lip pits as part of its expression. For non-syndromic CL/P, recent evidence suggests a single major gene may be causal in 1/3 of cases with the remainder multifactorially based. Rodent and in vitro human studies have suggested a role for growth factors or their receptors in CL/P. We propose to use naturally occurring DNA variants of growth factors (RFLPs) to characterize the major genes involved in VDWS and non-syndromic CL/P. Such characterization will not only serve to improve diagnosis, prevention and treatment of CL/P, but also will identify a paradigm for single gene disturbances of developmental regulation in man. We will begin by characterizing three groups of individuals with orofacial clefting: 500 probands with non-syndromic CL/P, 35 families with VDWS: and 100 sib pairs affected with non- syndromic CL/P. Complex segregation analysis to identify the role of a major gene will be done on families of the first group. A battery of growth factors, receptors and related genes will be obtained and characterized for restriction fragment length polymorphisms. These RFLPs will be used for association studies in the 500 non-syndromic CL/P individuals and for linkage analysis in the VDWS and affected sib pairs. The major genes identified in the association and linkage analysis will then be characterized using fine structure genetic mapping and DNA sequencing techniques.